Dr. Pergam completed an MPH degree and Infectious Diseases training at the University of Washington. This proposal describes a 5-year training program which will allow him to develop an independent academic career in clinical research studying the genetics of host immunity to cytomegalovirus (CMV) in transplant. This project will build on preliminary work evaluating the role of killer immunoglobulin-like receptors (KIR) in CMV infection in hematopoietic cell transplantation (HOT). CMV is the most common viral infection in HOT, with over 60% of seropositive recipients reactivating, and 9% developing life-threatening complications. Since natural killer (NK) cells recover quickly after transplantation, they may play an important role in the control of reactivation in the early post-transplant period. Our preliminary studies provide new evidence of an increased risk of invasive CMV disease.in recipients who receive only one donor activating KIR gene. We also show that individual donor KIR genes, particularly KIR3DS1, may decrease rates of both reactivation and invasive CMV disease. In addition, our data suggests that fewer cytotoxic CD56/KIR* natural killer cells in the post-HCT period increase the risk of CMV reactivation. In our first Aim, we will evaluate the associations between KIR and CMV quantitative phenotypes using a retrospective cohort of seropositive HOT recipients (Aim 1a). We will then sequence donor KIR3DL1/DS1 as a candidate gene, and assess it for associations with CMV pneumonia using a case control approach (Aim 1b). Finally, we will prospectively evaluate post-HCT NK cell and KIR reconstitution in the laboratory and determine how they affect CMV reactivation (Aim 2). Together, these studies will provide new insights into the role of NK cells in CMV immunobiology. RELEVANCE (See instructions): CMV remains the most common viral infection in transplantation, and is associated with significant morbidity and mortality. Through these genetic studies we hope to identify better predictors for CMV reactivation and disease, which could help to alter donor selection, identify appropriate candidates for aggressive antiviral prophylaxis pre-transplant, and may eventually lead to a reduction in the burden of CMV complications in HCT.